The clinical use of anthracyclines (e.g., doxorubicin) for the therapy of pediatric and adult cancers is hampered by the development of cardiotoxicity in some patients. In the breast cancer setting, the incidence of anthracycline-induced heart failure can be as high as ~26% depending on dose. The use of the anti-ERBB2 receptor antibody trastuzumab (Herceptin) plus anthracyclines can increase the incidence of clinical heart failure by ~5 fold in comparison to trastuzumab alone. Concomitant coronary heart disease (CHD), a prevalent comorbidity in adults with cancer, increases the risk for cardiotoxicity. Exposure to cardiotoxic chemotherapy is a major contributor to the high risk for cardiovascular mortality experienced by 3 million breast survivors in the US. The molecular basis of the increased risk for drug-induced cardiotoxicity in cancer patients with CHD remains to be elucidated. This fundamental gap in knowledge hampers the design and implementation of tailored clinical strategies to mitigate the development of cardiotoxicity in patients with cancer and CHD. The hallmark of CHD is the presence of cardiac cell hypoxia. We have obtained preliminary data indicating that the expression of key anthracycline metabolizing enzymes is increased in myocardial tissue from individuals with CHD. Also, we have recently shown that DNA methylation in the ERBB2 locus is a novel epigenetic determinant of the myocardial expression of the trastuzumab target ERBB2. Our objective now is to determine the contribution of these genetic, epigenetic, and metabolic changes to the increase in drug-induced cardiotoxicity in cancer patients with CHD. Based on exciting preliminary data, our central hypothesis is that the increased myocardial synthesis of cardiotoxic anthracycline metabolites and altered myocardial expression of ERBB2 associated with CHD are responsible for increased drug-induced cardiotoxicity. Studies in Aim 1 will determine the effect of cardiac cell hypoxia on the intracellular metabolism and toxicodynamics of anthracyclines. Aim 2 will determine the functional impact of the CBR3 V244M variant, a genetic risk factor for cardiotoxicity identified by us, on the toxicodynamics of anthracyclines in the context of cardiac cell hypoxia. Because of the well documented cardiotoxic interactions between anthracyclines and the ERBB2 inhibitor trastuzumab during treatment for breast cancer, studies in Aim 3 will determine the effects of differential ERBB2 methylation on the cardiotoxicity of trastuzumab. We will quantitatively assess associations between ERBB2 methylation status and cardiac ejection fraction in patients that had received trastuzumab for metastatic breast cancer. These integrative studies will provide new data to assist the design of more effective and less toxic therapeutic regimens for cancers affecting millions of Americans.